Degradation products of beclomethasone dipropionate in human plasma.
The anti-inflammatory glucocorticosteroid beclomethasone dipropionate was found previously to degrade in human plasma at 37 degrees C to yield beclomethasone 17-monopropionate, beclomethasone 21-monopropionate, and beclomethasone together with three unknown species, D-1, D-2, and D-3. In this paper, we report the isolation of D-2 and D-3 by preparative HPLC and the elucidation of their structures. Both products D-2 and D-3 exhibited UV bathochromic shifts relative to beclomethasone dipropionate of 9 nm. From the mass spectrometry and 1H-NMR data, it is concluded that D-2 and D-3 are formed from beclomethasone and beclomethasone 21-monopropionate, respectively, with the loss of hydrogen chloride and the formation of a 9,11-epoxide. Data for 1H-NMR methyl chemical shifts are used to show that the epoxide has the mechanistically more plausible 9beta,11beta configuration. Thus, D-2 is 9beta, 11beta-epoxy-16beta-methyl-1,4-pregnadiene-17alpha,21- diol-3, 20-dione, and D-3 is its corresponding 21-propanoate. The various enzyme-catalyzed and nonenzyme-catalyzed reactions involved in the degradation of beclomethasone dipropionate in human plasma are discussed. A degradation scheme is proposed.
Foe
K
K
Department of Pharmacy, University of Sydney, Australia.
Cheung
H T
HT
Tattam
B N
BN
Brown
K F
KF
Seale
J P
JP
D018927:Anti-Asthmatic Agents / Q000378:metabolism; D001507:Beclomethasone / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D008658:Inactivation, Metabolic / Q000502:physiology; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D013237:Stereoisomerism; D013256:Steroids / Q000032:analysis / Q000737:chemistry
D018927:Anti-Asthmatic Agents; D005938:Glucocorticoids; D013256:Steroids; D001507:Beclomethasone